Back to EveryPatent.com
United States Patent |
5,209,933
|
MacFarlane
,   et al.
|
May 11, 1993
|
Long acting calcium channel blocker composition
Abstract
There is disclosed an improved long acting sustained release pharmaceutical
composition for dihydropyridine calcium channel blockers wherein the
calcium channel blocker and a pH-dependent binder, which are intimately
admixed in essentially spherically shaped non-rugose particles of up to
1.2 mm in diameter, are provided with a coating to obtain slow, sustained
release of a safe, therapeutically effective amount of the calcium channel
blocker over a period of at least about 24 hours. Thus, the improved
pharmaceutical composition for a dihydropyridine calcium channel blockers
is suitable for once daily administration.
Inventors:
|
MacFarlane; Calum B. (Linlitchgow, GB6);
Selkirk; Alastair B. (Edinburgh, GB6);
Langridge; John R. (Edinburgh, GB6);
Dey; Michael J. (East Calder, GB6)
|
Assignee:
|
Syntex (U.S.A.) Inc. (Palo Alto, CA)
|
Appl. No.:
|
759792 |
Filed:
|
September 13, 1991 |
Current U.S. Class: |
424/494; 424/490; 424/497; 514/356 |
Intern'l Class: |
A61K 009/16 |
Field of Search: |
424/494,490,497
514/356
|
References Cited
U.S. Patent Documents
4343789 | Aug., 1982 | Kawata et al. | 428/78.
|
4665100 | May., 1987 | Ludwig | 514/77.
|
4704295 | Nov., 1987 | Porter | 424/497.
|
4758437 | Jul., 1988 | Sonobe | 424/471.
|
4765990 | Aug., 1988 | Sugimoto et al. | 424/494.
|
4816264 | Mar., 1989 | Phillips | 424/497.
|
4857312 | Aug., 1989 | Hegasy | 424/80.
|
4859665 | Aug., 1989 | Garthoff | 514/221.
|
4940556 | Jul., 1990 | MacFarlane | 264/15.
|
4970081 | Nov., 1990 | Frisbee | 424/497.
|
Foreign Patent Documents |
0267386 | Sep., 1987 | EP.
| |
Primary Examiner: Page; Thurman K.
Assistant Examiner: Phelan; D. Gabrielle
Attorney, Agent or Firm: Lowin; David A., Moran; Tom M.
Parent Case Text
This is a continuation of pending application Ser. No. 07/463,103, filed
Jan. 10, 1990, now abandoned, incorporated herein by reference.
Claims
What is claimed is:
1. In an improved long acting sustained release pharmaceutical composition
for administration of a therapeutically effective amount of a
dihydropyridine calcium channel blocking agent, useful in the treatment of
disease conditions that may be alleviated by the administration of calcium
channel blocking agents, which comprises essentially spherical,
non-coated, non-rugose particles having diameters up to 1.2 millimeter,
comprising a therapeutically effective amount of calcium channel blocking
agent in intimate admixture with at least about 3 weight percent of a
pH-dependent binder, which is less soluble below about pH 4.5 and more
soluble above about pH 5.5;
the improvement comprising providing said composition with a single
pH-dependent coating applied to said particles containing said calcium
channel blocking agent, which is less soluble below about pH 4.5 and more
soluble above about pH 5.5, to obtain slow, sustained release of a safe,
therapeutically effective amount of the calcium channel blocking agent
from said particles over a period of at least about 24 hours.
2. A composition according to claim 1 wherein the dihydropyridine calcium
channel blocking agent is a compound selected from the group represented
by the formula:
##STR7##
where; R.sub.1 is --NO.sub.2, --CF.sub.3, or halo;
R.sub.2 is alkyl or --CH.sub.2 CH.sub.2 OCH.sub.3 ; and
R.sub.6 is hydrogen or alkyl; and
R.sub.3 is alkyl, alkylenyloxyalkyl, haloalkyl, optionally substituted
phenyl alkyl, optionally substituted napthyl alkyl, or
##STR8##
in which: A is alkylene;
R.sub.4 is alkyl, alkoxy, or optionally substituted phenyl or phenyl alkyl;
and
R.sub.5 is hydrogen or alkyl;
and the pharmaceutically acceptable salts thereof.
3. A composition according to claim 2 wherein
R.sub.1 is --NO.sub.2,
R.sub.2 is CH.sub.3,
R.sub.3 is
##STR9##
R.sub.6 is H, and the hydrochloride salts thereof.
4. A composition according to claim 1 wherein the coating material is
selected from polyvinyl polymers and cellulose polymers.
5. A composition according to claim 4 wherein the coating material is a
polyvinyl polymer selected from the group of organic solvent soluble
polyvinyl acetate phthalate, aqueous dispersions of polyvinyl acetate
phthalate and aqueous dispersions of methacrylic acid methacrylate ester
copolymer.
6. A composition according to claim 4 wherein the coating material is a
cellulose polymer selected from the group of hydroxypropylmethylcellulose
phthalate, hydroxypropylmethylcellulose acetate and cellulose acetate
trimellitate.
7. An improved long acting sustained release pharmaceutical composition for
administration of a therapeutically effective amount of dihydropyridine
calcium channel blocking agent, useful in the treatment of disease
conditions that may be alleviated by the administration of calcium channel
blocking agents, comprising:
essentially spherical, non-coated, non-rugose particles having diameters up
to 1.2 millimeter, comprising a therapeutically effective amount of
calcium channel blocking agent in intimate admixture with at least about 3
weight percent of a pH-dependent binder, which is less soluble below about
pH 4.5 and more soluble above about pH 5.5; and
a pH-dependent, outermost coating, that is less soluble below about pH 4.5
and more soluble above about pH 5.5, to obtain slow, sustained release of
a safe, therapeutically effective amount of the calcium channel blocking
agent over a period of at least about 24 hours,
wherein said spherical particles comprise a composition of
______________________________________
Ingredient Weight %
______________________________________
Nicardipine HCL 44.4
Microcrystalline cellulose
18.5
Lactose 17.8
Methacrylic 18.5
acid ethylacrylate copolymer
Sodium hydroxide 0.4
Polyoxythylene 20 sorbitan
0.4
mono-oleate
______________________________________
and wherein the coating is applied to the particles as a suspension
comprising
______________________________________
Ingredient Weight %
______________________________________
Methacrylic 12.5
acid ethylacrylate copolymer
Triethylcitrate 1.25
Talc 6.25
Water 80.0
______________________________________
the coating suspension being present in an amount sufficient to coat the
particles with about 2-20% solids based on the weight of the uncoated
particles.
8. A long acting sustained release pharmaceutical composition for
administration of a therapeutically effect amount of dihydropyridine
calcium channel blocking agent consisting essentially of:
(a) non-rugose, spherical particles, up to 1.2 mm in diameter, comprising
the calcium channel blocking agent and a pH-dependent binder; and
(b) a pH-dependent, aqueous coating applied to each of said particles, said
coating comprising a compound selected from the group consisting of
polyvinyl acetate phthalate, methacrylic acid methacrylate ester
copolymer, methacrylic acid ethylacrylate copolymer,
hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose
acetate and cellulose acetate trimellitate;
said pH-dependent binder and said pH-dependent coating being less soluble
below about pH 4.5 and more soluble above about pH 5.5.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention concerns an improved long acting sustained release
pharmaceutical composition and dosage form for dihydropyridine calcium
channel blockers.
2. Description of Related References
Calcium channel blockers are a relatively recently discovered class of
compounds which possess a wide spectrum of properties useful in the
treatment of cardiovascular and cerebrovascular disorders. Among the
clinical applications for which this class of compounds has shown some
useful therapeutic properties are the treatment of classic exertional
angina, vasospastic angina, angina pectoris, acute myocardial infarction,
cardiac arrhythmias, systemic arterial hypertension, pulmonary arterial
hypertension, and cardiomyopathies.
Several structural classes of compounds are known which exhibit calcium
channel blocking utility. Compounds representative of some of these
classes include nicardipine, verapamil, diltiazam, perhexiline and
lidoflazine.
The structural class of calcium channel blockers of interest in this
invention, of which nicardipine is a member, are
1,4-dihydropyridine-3,5-dicarboxylic acid derivatives of the general
formula A:
##STR1##
in which AR is a simple or fused aryl or heteroaryl ring moiety; X is
hydrogen or one or more substituents on the AR moiety; R.sub.7 and R.sub.8
are independently hydrogen or ester forming moieties; R.sub.9 and R.sub.10
are independently methyl or various other 2 and 6 position substituents on
the dihydropyridine ring, and R is hydrogen or an alkyl or simple aryl
group. Examples of AR groups include, but are not limited to phenyl,
pyridinyl, benzofurazanyl, benzoxadiazolyl and the like. Examples of X
groups include, but are not limited to alkyl, halo, haloalkyl, alkoxy,
haloalkoxy, alkoxycarbonyl, alkenyl, methylenedioxy, ethylenedioxy, nitro,
cyano and the like. Examples of R.sub.7 and R.sub.8 ester forming moieties
include, but are not limited to alkyl, alkoxy, haloalkyl, nitro,
hydroxyalkyl, alkylenyloxyalkyl, phenylaminoalkyl, alkylaminoalkyl or
alkoxyaminoalkyl, amino(carbonyl)oxyalkyl, or an optionally substituted
simple or fused aryl, aralkyl or arylsulfonyl group such as, but not
limited to, phenyl, phenylalkyl, phenylsulfonyl, phenylalkenyl, naphthyl,
naphthylalkyl, dioxaphosphorinanyl, piperidinyl, pyrrolidinyl, furyl,
pyrrolyl, pyridyl, imidazolyl, thienyl, morpholinyl,
[(tetrahydropyran-2-yloxy)-alkyl]phenoxyalkyl or
[(tetrahydropyran-2-yloxy)-alkyl]phenylthioalkyl. Examples of R.sub.9 and
R.sub.10 substituents include, but are not limited to alkyl such as
methyl, a substituted alkyl group such as hydroxyalkyl or
aminoalkoxyalkyl, cyano, or optionally substituted phenylcarbonylalkyl;
Examples of R groups other than hydrogen include, but are not limited to
alkyl, benzyl, morpholinyl and morpholinylalkyl.
Many compounds within the general class represented by formula A are known
and have been shown to have calcium channel blocking activity. It is
known, for example, that
4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid
dimethyl ester shows calcium channel blocking activity (U.S. Pat. No.
3,644,627). Other compounds within this structural and pharmacologic class
include those disclosed in U.S. Pat. No. 3,511,837
(4-pyrimidyl-1,4-dihydropyridine derivatives), U.S. Pat. No. 3,691,177
(cyanophenyl-1,4-dihydropyridine derivatives), German Offlegungsschrift
No. 1,813,436 (N-alkyl-1,4-dihydropyridine derivatives), No. 1,963,185
(4-nitro and other group substituted phenyl-1,4-dihydropyridine
derivatives), No. 1,963,186 (sulfur containing 4-aryl-1,4-dihydropyridine
derivatives), No. 2,005,116 (1,4-dihydropyridine-3,5-dicarboxylic acid
unsaturated alkyl esters), No. 2,3,146
(3-alkanoyl-1,4-dihydropyridine-5-carboxylic acid esters, U.S. Pat. No.
3,511,837
(1,4-dihydro-2,6-dimethyl-4-(2'-trifluoromethylphenyl)-3,5-pyridine
dicarboxylic acid diethyl ester) and in BE 862-107, U.S. Pat. No.
4,017,629, DE 2,616,995, and German Offenlegungsschrift 3,501,695 (various
3-arylsulfonyl 1,4-dihydropyridine derivatives). Other 1,4-dihydropyridine
compounds with cardiovascular activity are disclosed in U.S. Pat. Nos.
3,644,627 and 3,485,847, in German Offenlegungsschrift 1,670,827 and in
Bundesrepublik Deutschland Auslegeschrift 17,92,764.
Specific compounds of formula A which can be incorporated in the long
acting sustained release composition of this invention include
2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-[3-(4-[2-(tetrahydropyran-
2-yloxy)ethyl]phenoxy)propoxy carbonyl]-1,4-dihydropyridine disclosed in
U.S. application Ser. No. 874,264 filed Jun. 13, 1986, now U.S. Pat. No.
4,761,420 issued Aug. 2, 1988, the disclosure of which is incorporated by
reference herein; 3,5-pyridinedicarboxylic acid,
2-[(2-aminoethoxy)methyl]-4-(2-chlorophnyl)-1,4-dihydro-6-methyl, 3-ethyl
5-methyl ester, (.+-.)-, (Z)-2-butenedioate, generic name: amlodipine;
3,5-pyridinedicarboxylic acid
4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-, diethyl ester, generic
name: darodipine; 3,5-pyridinedicarboxylic acid,
1,4-dihydro-2,6-dimethyl-1-[2-(4-morpholinyl)ethyl]-4-[2-(trifluoromethyl)
phenyl]-, diethyl ester, generic name: flordipine;
1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethyl-phenyl)-3,5-pyridinedicarbox
ylic acid 2-([1-(4-hydroxyphenyl)-3-oxopropyl]amino)ethyl ester), generic
name: iodipine; isopropyl methyl 4-(4-benzofurazanyl)-1,4
-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate, generic name: isodipine;
diethyl
1',4'-dihydro-2',6'-dimethyl-2-(methylthio)[3,4'bipyridine]-3'5'-dicarboxy
late, generic name: mesudipine; 3,5 pyridinedicarboxylc acid,
2-cyano-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-, 3-methyl
5-(1-methylethyl) ester, generic name; nilvadipine; ethyl methyl
1,4-dihydro-2,6-dimethyl-4-[2,3-(methylenedioxy)-phenyl-3,5-pyridinedicarb
oxylate, generic name: oxodipine; dimethyl
4-[o-(di-fluoromethyl)phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridine
dicarboxylate, generic name: riodipine; methyl
2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-
dihydropyridine 3-carboxylate;
1,4-dihydro-2-hydroxmethyl-4-(m-nitrophenyl)-6-methyl-3,5-pyridine
dicarboxylic acid diethyl ester; methyl (E)-3-phenyl-
2-propeny-1-yl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dica
rboxylate;
(E)-4-(2-(3-(1,1-dimethylethoxy)-3-oxo-1-propenyl)phenyl-1,4-dihydro-2,6-d
imethyl-3,5-pyridinedicarboxylic acid, diethyl ester;
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid
methyl 1-(phenylmethyl)-3-piperidinyl ester monohydrochloride;
3-(2-furoyl)-5-methoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydrop
yridine; 3,5-pyridinedicarboxylic acid
2-(((aminocarbonyl)oxy)methyl)-4-(2,3-dichlorophenyl)-1,4-dihydro-6-methyl
-5-methyl 3-(1-methylethyl)ester; 1-benzyl-3-pyrrolidinyl methyl
2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate; and
isopropyl
4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridineca
rboxylate.
Calcium channel blockers of particular interest in this invention are
compounds selected from the group represented by the formula:
##STR2##
where;
R.sub.1 is --NO.sub.2, --CF.sub.3, or halo;
R.sub.2 is alkyl or --CH.sub.2 CH.sub.2 OCH.sub.3 ; and
R.sub.6 is hydrogen or alkyl; and
R.sub.3 is alkyl, alkylenyloxyalkyl, haloalkyl, optionally substituted
phenyl alkyl, optionally substituted napthyl alkyl, or
##STR3##
in which:
A is alkylene;
R.sub.4 is alkyl, alkoxy, or optionally substituted phenyl or phenyl alkyl;
and
R.sub.5 is hydrogen or alkyl;
and the pharmaceutically acceptable salts thereof.
Several compounds within this group are known to possess a high degree of
calcium channel blocking activity. These include, for example,
4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid
dimethyl ester, generic name: nifedipine (U.S. Pat. No. 3,644,627);
4-(3'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid
di-n-propyloxethyl ester, generic name: niludipine;
4-(3'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid
3-ethyl ester 5-methyl ester, generic name: nitrendipine;
4-(3'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid
3-methyl ester 5-(2-methoxyethyl)ester, generic name: nimodipine;
4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid
3-methyl ester 5-isobutyl ester, generic name: nisoldipine;
4-(2',3'-dichloro)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid
3-ethyl ester 5-methyl ester, generic name: felodipine;
4-(3'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid
3-methyl ester 5-.beta.-(N-benzyl-N-methylamino)-ethyl ester, generic
name: nicardipine; isopropyl methyl 1,4-dihydro-2,6-dimethyl
4-(3-nitrophenyl)-3,5 -pyridine dicarboxylate; and
2,6-dimethyl-3,5-diethoxycarbonyl-4-(o-difluoromethylphenyl)-1,4-dichydrop
yridine.
Other compounds of Formula I which can be practically administered from the
long acting sustained release compositions of this invention include
2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-phenyl-1,4-dihydropyridine,
2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(3-methylphenyl)-1,4-dihydropyridi
ne,
2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(3-cyanophenyl)-1,4-dihydropyridin
e,
2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridin
e,
2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(4-nitrophenyl)-1,4-dihydropyridin
e,
2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(4-methylphenyl)-1,4-dihydropyridi
ne,2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-[4-(dimethylamino)phenyl]-1,4-di
hydropyridine, 2,6-dimethyl-4-phenyl-1,4-dihydropyridine 3,5-dicarboxylacid
diethyl ester,
2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(2,4-dinitrophenyl)-1,4-dihydropyr
idine,
2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-[2-(trifluoromethyl)phenyl)-1,4-di
hydropyridine, and
2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-(pentafluorophenyl)-1,4-dihydropyr
idine, all of which are disclosed in J. Med. Chem (1986) 29 (12), pp.
2504-2511.
Calcium channel blockers of the 1,4-dihydropyridine class share a number of
pharmacological and pharmacokinetic properties in common which render them
well suited to administration by the long acting sustained release methods
of this invention. They are drugs which are extensively lipid-soluble and
therefore are widely and extensively distributed within body tissues at
steady state. They are also rapidly absorbed after oral administration,
showing peak plasma levels within approximately about one hour
(T.sub.max). The half-life of elimination of these compounds is generally
in the range of two to five hours, thus necessitating administration of
standard oral dosage forms three to four times daily.
Additionally, some of the compounds, in particular, nicardipine, undergo
extensive first pass metabolism.
The pharmaceutical compositions and dosage forms of this invention are
particularly well suited for the administration of nicardipine and its
pharmaceutically acceptable salts, such as nicardipine and hydrochloride.
The preparation and use of nicardipine and other closely related compounds
and their pharmaceutically acceptable salts are described in U.S. Pat. No.
3,985,758, the disclosure of which is incorporated by reference herein.
At the present time, the preferred route of administration for most
therapeutic applications of the dihydropyridine calcium channel blockers
is via an oral dosage form. These are typically compressed tablets, hard
gelatin capsules filled with a powder mix, or soft gelatin capsule filled
with a solution, and are conventionally administered three or four times
daily.
However, conventional release oral dosage forms are poorly suited to
dihydropyridine calcium channel blocker therapy. At the low pH that often
occurs in the stomach, the solubility of the basic dihydropyridines is
relatively high, resulting in rapid dissolution and absorption. At higher
gastro-intestinal pH values, dihydropyridine solubility, and hence the
dissolution rate, decreases. As a result, conventional release oral dosage
forms release calcium channel blocker more rapidly in the more acidic
regions and less rapidly in the less acidic regions of the
gastrointestinal tract. The release profiles of such dosage forms are
inherently dependent upon the local pH.
There is a need, therefore, for a long acting dosage form with sustained
release properties capable of providing therapeutic calcium channel
blocker plasma concentrations when the dosage form is administered less
frequently, preferably once or twice daily. In addition to providing
convenience for the patient, such a sustained release dosage form would
minimize undesirable fluctuations in drug plasma concentration.
In Kawata et al., U.S. Pat. No. 4,343,789, formulations and dosage forms
for nicardipine and related compounds are described which provide some
dissolution control, and hence sustained release of the drug. As described
in the patent, there is formed a powder containing amorphous nicardipine,
polyethylene oxide, and other excipients which can then be formed into
granules, tablets, pills or capsules by conventional means. The
formulation requires that the nicardipine or salt thereof be in amorphous
form, and be combined with polyethylene oxide in a fine particle powder or
granules. The formulation may additionally contain a pH-dependent agent
for dissolution control, such as a copolymer of methacrylic acid and a
methacrylic acid ester. While the specific disclosure is primarily
directed to tablet formulations, one capsule dosage form is disclosed (in
Example 9) which contains small coated pills obtained by film coating a
mixed powder containing nicardipine hydrochloride with a solution of
methyl cellulose in water, and then further coating part of the coated
pills with an organic solution of Eudragit (methacrylic acid/methyacrylic
acid ester copolymer).
However, the preparation of the drug in amorphous form and the
incorporation of polyoxyethylene are time consuming and expensive
manufacturing procedures. Other granular and particulate calcium channel
blocker compositions formulated with a pH-dependent binding agent are
known. However, the manufacture of these compositions has required the use
of an organic solvent, which must subsequently be removed by arduous and
lengthy drying procedures and always leaving the risk of toxic residues.
Ludwig, U.S. Pat. No. 4,665,100, discloses a method of formulating a
synthetic drug for use in a feed which will reduce the carryover of the
drug from one lot of feed to a subsequent lot in feed mill operations. The
patented process involves intimately mixing the drug (about 1-40% of
minigranule on a dry weight basis) with a carrier (50-98% on a dry weight
basis), a physiologically acceptable binder (about 1-10% on a dry weight
basis), and water, extruding the mixture through a perforated plate having
relatively small apertures (about 0.5-1.5 mm) into elongated strands of
extrudate, and contacting the elongated strands of extrudate with a moving
frictional plate, imparting motion to said extrudate and developing a
tumbling, rolling bed thereof wherein the strands are reduced to nearly
spherical particals, called minigranules, drying them to remove excess
moisture, and seiving the minigranules through meshed wire screens to
obtain desired particle size.
Sugimoto et al., U.S. Pat. No. 4,765,990 (Aug. 23, 1988), disclose a
sustained-release preparation containing nifedipine which comprises a
Composition A and Composition B in a ratio of 15:85 to 50:50 by weight of
nifedipine. Composition A is a rapid-release preparation containing as an
active ingredient nifedipine fine powder of not more than 5 microns.
Composition B is a delayed-release preparation containing as the active
ingredient nifedipine fine powder having an average particle size of not
more than 5 microns and having a surface coating layer comprising a
non-toxic, hardly water-soluble substance and an enteric high molecular
compound.
EP 0,267,386 (Derwent Abstract 88-134312/20) discloses solid, sustained
release nifefipine dosage forms comprising, nifedipine and low-viscosity
ethyl cellulose on a carrier comprising a hydroxyalkyl cellulose, a sugar
and starch.
There is disclosed in U.S. Ser. No. 057,469 filed Jul. 26, 1987, now U.S.
Pat. No. 4,940,596, owned in common by the assignee of this application
for patent, a composition which was conceived for the purpose to overcome
some of what were perceived as disadvantages or deficiencies of the
references mentioned above, particularly with respect to Kawata et al.,
U.S. Pat. No. 4,343,789. The composition of the above-mentioned patent
application comprises essentially spherical, non-coated, non-rugose
particles having diameters up to 1.2 mm, comprising an effective amount of
a calcium channel blocker in intimate admixture with at least 3 weight
percent of a pH-dependent binder which is less soluble at lower pH and
more soluble at higher pH. This composition provides therapeutic plasma
concentrations of calcium channel blocker suitable for twice daily
administration of the pharmaceutical composition.
Although the pharmaceutical composition described in the preceding
paragraph is quite useful and effective and represents an improvement over
the art described in the foregoing passages, there remains a need for a
pharmaceutical composition which (1) provides therapeutically effective
dihydropyridine calcium channel blocker plasma levels when administered
even less frequently than twice daily, (2) avoids the risk of the
phenomenon of "dose dumping," which is essential at the higher doses given
once daily (3) provides readily and economically manufacturable
drug-containing particles of substantially uniform and regular size and
shape suitable for incorporation in hard gelatin capsules and other oral
and parenteral dosage forms and uses the thermodynamically stable powder
form of the drug thereby avoiding the inherent physical stability and
consequent changing bioavailability of a thermodynamically unstable
amorphous form.
SUMMARY OF THE INVENTION
This invention is an improved long acting sustained release pharmaceutical
composition for dihydropyridine calcium channel blockers wherein the
calcium channel blocker and a pH-dependent binder, which are intimately
admixed in essentially spherically shaped non-rugose particles of up to
1.2 mm in diameter, are provided with a coating to obtain slow, sustained
release of a safe, therapeutically effective amount of the calcium channel
blocker over a period of at least about 24 hours and to thereby provide
for once daily administration.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a graph showing nicardipine HCl levels in humans over a period of
24 hours for formulations comprising uncoated marumes (non-rugose
spherical particles), coated marumes and coated marumes plus fast release
powder; and
FIG. 2 is a graph showing nicardipine HCl levels over a period of 24 hours
for pdr[30], 30 mg fast release powder; coated [120], 120 mg coated
marumes; and pdr[20], 20 mg fast release powder.
DETAILED DESCRIPTION OF THE INVENTION
More particularly, this invention is, in an improved long acting sustained
release pharmaceutical composition for administration of a therapeutically
effective amount of a dihydropyridine calcium channel blocking agent,
useful in the treatment of disease conditions that may be alleviated by
the administration of calcium channel blocking agents, which comprises
essentially spherical, non-coated, non-rugose particles having diameters
up to 1.2 mm, comprising a therapeutically effective amount of calcium
channel blocking agent in intimate admixture with at least about 3 weight
percent of a pH-dependent binder which is less soluble at lower pH and
more soluble at higher pH:
the improvement comprising providing said composition with a coating to
obtain slow, sustained release of a safe, therapeutically effective amount
of the calcium channel blocking agent over a period of at least about 24
hours and to thereby provide for once daily administration.
DEFINITIONS
As used herein, the following terms have the meaning described below unless
otherwise indicated:
The term "alkyl" refers to a straight or branched hydrocarbon chain having
from one to six, preferably one to four carbon atoms. Examples of alkyl
groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl
and t-butyl.
The term "alkoxy" means a moiety of the formula --OR in which R is alkyl as
defined above.
The term "alkylenyl" means a straight or branched chain bivalent alkyl
bridging group.
The term "alkylenyloxyalkyl" means a moiety of the formula --R.sub.a OR in
which R.sub.a is alkylenyl and R is alkyl as defined above.
The term "halo" refers to chloro, bromo, iodo and fluoro. Nitro is a
preferred halo substituent on the phenyl ring of the 1,4-dihydropyridyne
calcium channel blockers compounds of interest in this invention.
The term "aryl" refers to homocyclic and heterocyclic moieties which are
substantially aromatic in character. Examples of aryl groups are phenyl,
naphthyl, imidazolyl, pyrrolyl, pyridinyl, thienyl, benzofurazanyl,
benzoxadiazolyl and the like. The term "aralkyl" refers to a alkylaryl
moieties.
The terms "phenyl alkyl" and "napthyl alkyl" mean radicals of the
structure:
##STR4##
respectively, in which R is alkyl as defined above. In the case of the
phenyl alkyl group, R may be in an.o-, m-or p-position. In the case of the
napthyl alkyl group, R may be in the 5-, 6-, 7-, or 8-position.
Unless otherwise indicated or defined, a chemical substituent name which
consists of compounded chemical group names is written in the order of
appearance of the individually named groups starting with the terminus of
the substituent. For example, "hydroxyalkyl" means a substituent of the
formula --ROH where R is alkyl, and "alkoxyaminoalkyl" means a substituent
group of the general formula --RNOR in which both R's are alkyl.
The terms "optional" and "optionally" mean that the subsequently described
event or circumstance may or may not occur, and that the description
includes instances where said event or circumstance occurs and instances
in which it does not. For example, "optionally substituted phenyl" means
that the phenyl moiety may or may not be substituted and that the
description includes both substituted and unsubstituted phenyl. The phrase
"optional pharmaceutical excipients" indicates that a composition or
dosage form so described may or may not include pharmaceutical excipients
other than those specifically stated to be present, and that the
formulation or dosage form so described includes instances in which
optional excipients are present and instances in which they are not.
The term "pharmaceutically acceptable acid addition salts" refers to salts
of the subject compounds which possess the desired pharmacological
activity and which are neither biologically nor otherwise undesirable.
These salts are formed with inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid and the
like; or organic acids such as acetic acid, propionic acid, glycolic acid,
pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid,
fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid and the like.
"Dihydropyridine calcium channel blocker" refers generally to any compound
which contains the dihydropyridine dicarboxylic acid moiety and has
calcium channel blocking activity. The compounds of formulas A and I
described above in the Background of the Invention are representative of
the dihydropyridine calcium channel blockers intended for use within the
scope of this invention. Dihydropyridine calcium channel blockers not
specifically described here may be beneficially administered from, and are
included within the scope of, this invention.
"Nicardipine" identifies the compound
2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic
acid-3-.beta.-(N-benzyl-N-methylamino)-ethyl ester 5-methyl ester, or any
of its pharmaceutically acceptable salts. The salt, nicardipine
hydrochloride, is the preferred calcium channel blocker of this invention.
The terms "treating" and "treatment" refer to any treatment of a disease in
a mammal, particularly a human, and include: (i) preventing the disease
from occurring in a subject which may be predisposed to the disease but
has not yet been diagnosed as having it;
(ii) inhibiting the disease, i.e., arresting its development; or
(iii) relieving the disease, i.e., causing regression of the disease.
The terms "fast release" and "conventional release" refer to calcium
channel blocker composition that are substantially completely dissolved
and absorbed in the stomach or upper gastrointestinal tract.
The terms "long acting" and "sustained release" refer to calcium channel
blocker compositions that are slowly and continuously dissolved and
absorbed in the stomach and gastrointestinal tract over a period of at
least two hours. Preferred long acting compositions and dosage forms
exhibit plasma concentration profiles suitable for once daily
administration of the dosage form.
The pharmaceutical compositions, dosage forms and methods of the invention
can be used to provide long acting sustained release administration of any
of the 1,4-dihydropyridine derivatives having calcium channel blocking
activity. The preferred dihydropyridine calcium channel blockers of this
invention are selected from the group represented by the formula:
##STR5##
where;
R.sub.1 is --NO.sub.2, --CF.sub.3, or halo;
R.sub.2 is alkyl or --CH.sub.2 CH.sub.2 OCH.sub.3 ; and
R.sub.6 is hydrogen or alkyl; and
R.sub.3 is alkyl, alkylenyloxyalkyl, haloalkyl, optionally substituted
phenyl alkyl, optionally substituted napthyl alkyl, or
##STR6##
in which:
A is alkylene;
R.sub.4 is alkyl, alkoxy, or optionally substituted phenyl or phenyl alkyl;
and R.sub.5 is hydrogen or alkyl;
and the pharmaceutically acceptable salts thereof.
The long acting sustained release pharmaceutical composition of the
invention contains particles of calcium channel blocking agent which are
coated spheroids, that is, essentially spherical particles having
substantially smooth, non-rugose surfaces which are coated with a coating
material, preferably a coating material which is poorly soluble at about
pH 4.5 and below, but readily soluble at, about pH of 5.5 and above. In
contrast to conventional granules, which may be approximately spherical in
their outermost surface dimensions, but are actually loose particulate
aggregates with highly rugose surfaces and area radius to circumference
radius ratios in the range of 0.6 to 0.8, the spheroids used in the
composition according to this invention have area radius to circumference
radius ratios in the range of 0.85 to 1.0, preferably in the range of 0.9
to 1.0. As used herein area radius is given by the formula:
the square root of [the projected area divided by pi], and the
circumference radius is given by the formula:
the projected circumference divided by 2 pi.
The projected area and projected circumference including indentations or
projections are determined from a projected image of the particles in
question. As used herein, "non-rugose" refers to an outer surface which is
substantially lacking in wrinkles, craters and other surface
irregularities. The terms "spheroids" and "spherical particles" are used
interchangeably herein.
Further in contrast to conventional granules, the spheroids of this
invention are relatively dense. Whereas conventional granules have
variable and significant degrees of porosity in the range of about 30-50%
internal void volume (see for example, Chalmers A. A. and Elworthy P. H.
(1976) J. Pharm. Pharmacol., 28, 239-243), the spheroids of this invention
have substantially decreased porosities in the range of less than about
20% internal void volume, preferably 15% internal void volume or less. The
smooth surface and low porosity of the spheroids provide substantially
greater dissolution control than can be achieved with conventionally
manufactured granules.
The spheroids and their preparation are disclosed and claimed in U.S. Ser.
No. 057,469 filed Jul. 26, 1987, now U.S. Pat. No. 4,940,596 owned in
common by the assignee of this application. Spheroids used in this
invention are prepared from an essentially aqueous, wet mass containing
the calcium channel blocker, pH-dependent binder, and any optional
pharmaceutical excipients. The term "essentially aqueous, wet mass" refers
to a powder mass which has been wetted with an essentially aqueous binding
solution to a consistency suitable for extrusion. The powder mass is made
by dry-blending the active ingredient(s) and any desired optional
pharmaceutical excipients such as a diluent. The term "essentially
aqueous" means that water is the predominant liquid in the binding
solution, which may include, but preferably will not include, up to 25%
other water-miscible solvents.
In the preferred embodiments of the spheroids, the pH-dependent binder may
be dissolved or dispersed in the aqueous binding solution which is used to
wet the dry powder mass or it may in some instances be preferable to
include some or all of the pH-dependent binder in the dry powder mass
prior to wetting with water or other essentially aqueous binding solution.
Whether the pH-dependent binder is included in the dry powder mass or in
the aqueous wetting solution, or both, the mixing of components which
takes place to form and extrude the wet mass should be sufficient to place
the active agent in intimate and substantially uniform admixture with the
binder and any other excipients which may be incorporated.
In addition to, and intimately admixed with the calcium channel blocker and
the pH-dependent binder in the wet mass may be other optional
pharmaceutically acceptable excipients. These may include diluents such as
lactose, mannitol, dry starch, microcrystalline cellulose and the like,
additional binders such as starch, gelatin, sugars,
carboxymethylcellulose, methylcellulose and the like, lubricants such as
talc and magnesium stearate, neutralizing agents such as sodium hydroxide,
potassium hydroxide and the like, surface active agents such as
polyoxyethylene sorbitan esters, sorbitan esters and the like, coloring
agents and flavoring agents.
The wet mass is then extruded to form rod-shaped, substantially cylindrical
segments having diameters in the range of up to 1.2 millimeters. As used
herein, the term "extrusion" refers to a process whereby a cohesive
rod-shaped, substantially cylindrical material of specific cross section
is formed by forcing the wet mass, from a wide diameter reservoir, through
an orifice of small diameter, such that the product substantially retains
the cross section of the orifice. These rod-shaped segments can then be
formed into spheres, as described below, and it is therefore important
that they be substantially cylindrical and of relatively uniform cross
section. The extrusion step should also impart additional density (low
porosity) to the material, which may be further densified during the
spheronization step.
There are a wide variety of such extrusion methods known and available in
the pharmaceutical industry. In general, these methods rely on generation
of a continuous pressure of sufficient magnitude to induce the material to
flow and retain the shape of the die on exit. The degree of wetness, flow
and cohesive properties of the wet mass also affect the quality and
uniformity of the extruded material. Well known, standard types of
extrusion equipment suitable for use in this invention include screw
extruders, cylinder extruders, gear extruders, ram extruders and radial
screen rotating head type extruders.
The extruded rod-shaped segments are then shaped into spherical particles,
which when dry and optionally coated, are long acting sustained release
spheroids suitable for use in a variety of oral and parenteral dosage
forms. As discussed above, in order to provide the desired prolonged
dissolution and release profiles, the outer surface of the spheroids must
be substantially smooth, non-rugose and essentially spherical.
Spheronization equipment capable of forming spheroids having the desired
properties from cylindrical extrudate is commercially available. For
example, the Marumerizer machine (Conine J. W. and Hadley H. R., (1970)
Drug Cosmet. Ind., 106, 38-41) can be used to provide spherical particles
of suitable surface smoothness and regularity of size and shape. In the
Marumerizer, the rod-shaped segments of extrudate are shaped into
spheroids by centrifugal and frictional forces on a rotating disc or pan.
This method of spheronization offers the opportunity to regulate the size
of the spherical particles.
The dried, spherical granules may be film coated with a polymer in a
variety of equipment such as an open rotating pan, a side vented rotating
pan (e.g. Manesty Accelacota.RTM.), a fluidized bed coating column or a
Wurster column. All of these machines provide a means of mixing and drying
the spherical granules and at the same time applying a solution or
suspension of the coating polymer in an organic, or preferably
substantially aqueous, medium. The coated and dried spherical granules may
optionally then be blended with an agent such as talc or collodial silicon
dioxide or the like to reduce static charges and facilitate subsequent
handling.
The spheroids may be varied in size up to about 1.2 mm, and the size of the
spheroids can be adjusted to control the rate of spheroid dissolution and
drug release. Smaller spheroids have higher surface to volume ratios, and
hence faster dissolution rates, than larger spheroids. The preferred size
for spheroids is between about 0.5 mm and 1.2 mm, most preferably between
about 0.7 mm and 1.0 mm. It is also preferred that the size distribution
of the spheroids be as narrow as possible; spheroids within a narrow size
distribution range provide a plasma concentration profile which is more
flat and constant than that achieved with particles of widely differing
sizes. In the preferred embodiments, at least 70 weight percent of the
spheroids used in the compositions according to this invention will have
diameters which are within upper and lower limits differing by not more
than a factor of the square root of two from each other.
In order to provide sustained release of the dihydropyridine calcium
channel blocker, the binder and coating materials suitable for use in the
spheroids used in this invention must control the dissolution profile of
the drug-containing spheroids so that they dissolve slowly and
continuously throughout their passage within the stomach and along the
gastrointestinal tract. The dissolution control capacity of the binding
and coating agent is particularly important in a long-acting dosage form;
a sustained release dosage form which contains sufficient drug for once or
twice daily administration may cause untoward side effects if it dissolves
too rapidly and dumps all of the drug into the gastrointestinal tract in a
short period of time.
Accordingly, binders and coating materials suitable for use in the
spheroids used in this invention are materials which prevent rapid
dissolution of drug from the spheroids during their residence in those
regions of the gastrointestinal tract where the pH is about 4.5 or less,
and allow dissolution of the drug from the spheroids in the small and
large intestines (where the pH is generally greater than about 5.5). Any
material which is pharmaceutically acceptable for oral ingestion and which
can impart such dissolution control to the calcium channel blocker
spheroids can be used in this invention. Generally these materials are
substantially insoluble at a pH of less than about 4.5 and are soluble at
a pH of greater than about 5.5. Many materials known in the pharmaceutical
art as "enteric" binders and coating agents have the desired properties.
These include a large number of phthalic acid derivatives such as the
phthalic acid derivatives of vinyl polymers and copolymers,
hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates,
hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose acetates,
and the partial esters thereof; and polymers and copolymers of lower alkyl
acrylic acids and lower alkyl acrylates, and the partial esters thereof.
Examples of specific pH-dependent binder materials which may be used
include hydroxypropyl cellulose phthalate, cellulose acetate phthalate,
polyvinylacetate phthalate, polyvinylpyrrolidone phthalate,
hydroxypropylmethyl cellulose phthalate and copolymers of methacrylic acid
and methacrylic or acrylic acid esters. Particularly preferred binders for
use in this invention are the commercially available copolymers of
methacrylic acid and a methacrylic or acrylic acid ester, for example the
Eudragit polymers, particularly the Eudragit L series such as Eudragit
L30D and Eudragit L100/55, sold by the Rohm and Haas Company. Eudragit
L100-55 and Eudragit L30D (a dispersion of 30% Eudragit L powder in water)
are the preferred pH dependent binder and coating materials for use in
this invention. It is to be noted that viscosity enhancing agents such as
hydroxypropylmethylcellulose, methylcellulose and polyvinylpyrolidone
which dissolve at a rate independent of pH, do not provide the required
dissolution control.
The spheroids may contain the calcium channel blocker in any proportion
from as little as 1 weight percent or less up to about 95 weight percent.
The pH-dependent binder may be present in any proportion from as little as
3 weight percent up to about 95 weight percent. While the proportion of
active agent present will depend largely on its potency, the proportion of
pH-dependent binder will depend on the degree of release rate control
which is needed for the particular active agent. Generally, the
pH-dependent binder will constitute about 5 to 50 weight percent,
preferably about 5 to 25 weight percent of each spherical particle. A
preferred spheroid composition for the administration of nicardipine
hydrochloride will contain about 40 to 50 weight percent nicardipine
hydrochloride and about 5 to 25 weight percent pH-dependent binder, with
the remainder being fillers, binders and other optional excipients. A
particularly preferred spheroid composition for the administration of
nicardipine hydrochloride is:
______________________________________
Ingredient Weight %
______________________________________
Nicardipine HCL 44.4
Microcrystalline cellulose
18.5
Lactose 17.8
Eudragit L100-55 18.5
Sodium hydroxide 0.4
Polyoxyethylene 20 sorbitan
0.4
mono-oleate
______________________________________
The coating material may be selected from any conventional enterocoating
material which is known to those skilled in the art to which this
invention relates. Suitable coating materials include those binder
materials listed above. Preferably, both the spheroid partical containing
the active ingredient calcium channel blocking agent and the coating
provide sustaining action at pH values below about 5.5.
Suitable coating materials include polyvinyl derived polymers and cellulose
derived polymers and these may be in the form of organic solvent soluble
polymers or aqueous dispersions of the polymers.
Specific suitable polyvinyl derived polymers include the following to name
but a few: polyvinyl acetate phthalate (PVAP, Mfr. by Colorcon, pH 4.8,
organic solvent soluble); aqueous colloidal dispersion of PVAP
(COATERIC-TM, Mfr. by Colorcon, pH 5.0); aqueous dispersion of methacrylic
acid methacrylate ester copolymer (Eudragit L, Mfr. by Rohm Pharma, pH
5.5).
Specific suitable cellulose derived polymers include
hydroxypropylmethylcellulose phthalate (HPMCP, Mfr. by Shin Etsu, HP-50-TM
pH 5 and HP-55 pH 5.5, organic solvent soluble);
hydroxypropylmethylcellulose acetate (HPMC-AS-TM, Mfr. by Shin Etsu, pH
5.0 or 5.5, organic solvent soluble;); cellulose acetate trimellitate
(CAT-TM, Mfr. by Eastman Kodak, pH 5.5, organic solvent soluble).
A preferred coating suspension for the spheroids is:
______________________________________
Ingredient Weight %
______________________________________
Eudragit L 12.5
Triethylcitrate
1.25
Talc 6.25
Water 80.0
______________________________________
The spheroids are coated with the suspension in a quantity preferrably of
about 2-20% (solids) of the spheroid weight. A more preferred quantity is
3-10% (solids) of the spheroid weight.
UTILITY AND ADMINISTRATION
Depending on the particular calcium channel blocker which is incorporated,
the pharmaceutical compositions and dosage forms of the invention may be
used for treating a wide variety of disease states which involve one or
more forms of cardiovascular and cerebrovascular disfunction. The calcium
channel blockers of interest in the invention generally possess a broad
spectrum of cardiovascular and cerebrovascular activities including
anti-anginal and antihypertensive properties. Nicardipine also possesses
anti-ischemic properties. The invention compositions can therefore be
beneficially used in treating cardiovascular and cerebrovascular disorders
in patients who are susceptible to calcium ion entry blockade.
The preferred method of administration of these compositions is oral,
except in those cases where the patient is unable to ingest, by himself,
medication. The preferred oral dosage forms of the invention are capsules,
preferably hard gelatin capsules, which contain the long acting spheroids
in amounts suitable for the desired dosage period. Other dosage froms for
oral administration include powders or spherical particulates for
ingestion with foods or beverages.
Because the coated spherical particle compositions of the invention exhibit
a prolonged release profile at physiological pH values, they can also be
formulated in parenteral suspensions or slow release depot formulations
for subcutaneous or intramuscular injection. The parenteral dosage forms
can be be prepared by suspending the spheroids and optional pharmaceutical
adjuvants in a carrier, such as, for example, water, saline solutions,
aqueous dextrose, glycerol and the like. The dosage form may also contain
minor but effective amounts of non-toxic auxiliary substances such as
wetting and emulsifying agents, pH buffering agents and the like, for
example, sodium acetate, sorbitan monolaurate, triethanolamine sodium
acetate, triethanolamine oleate and the like. Actual methods of preparing
such dosage forms are known, or will be apparent to those skilled in this
art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing
Company, Easton, Pa., 15th Edition, 1975.
The compositions and dosage forms of the present invention provide several
therapeutic advantages. Because of the long-acting properties of the
coated spheroids, the pharmaceutical compositions and dosage forms of the
invention can be designed to provide therapeutic calcium channel blocker
plasma concentration profiles suitable for once daily administration. The
long acting spheroids may be administered alone or in combination with a
conventional powder blend of a calcium channel blocker. In measurements of
drug plasma concentration versus time, the improved long acting
compositions of the invention provide therapeutic plasma concentrations
for a period at least about 24 hours when administered once daily so as to
provide substantially the same benefit and advantages afforded by the
twice-daily composition according to U.S. Ser. No. 057,469 filed Jul. 26,
1987; now U.S. Pat. No. 4,940,556 without the disadvantages of the
instantaneous discharge of high amounts of active ingredient above the
amount which can be absorbed before elimination from the patient as is
ordinarily observed when administering such high dose of active
ingredient.
The following examples are exemplary of the invention described in the
specification and claims. They are not to be construed as limiting the
scope of the claims.
COMPARISON--EXAMPLE 1
Preparation of Fast Standard Release Powder
A. 2.4 kg nicardipine hydrochloride and 17.5 kg pregelatinized starch were
blended for 20 minutes in a Hobart mixer. 0.1 kg of magnesium stearate was
then added and blended for 3 minutes.
B. In like manner, fast release powder compositions may be prepared from
other dihydropyridine calcium channel blocker including nifedipine,
niludipine, nitrendipine, nisoldipine, nimodipine, and felodipine.
COMPARISON--EXAMPLE 2
Preparation of Long Acting Spheroids
A. 1.8 kg of nicardipine hydrochloride, 0.72 kg of microcystalline
cellulose and 1.5 kg of Eudragit L100-55 (brand copolymer of methacrylic
acid and ethylacrylate) were blended togehter in a Hobart mixer. A
solution of 0.03 kg of sodium hydroxide in water was added to the dry
mixture and the wet mass was further mixed. The wet mass was extruded
through a Nica extruder having a screen size of 0.8 mm and the extrudate
was rotated on a Nica spheroniser at about 400 rpm for about 3 minutes.
The spheronised particles were then dried in an Aeromatic fluid bed drier
at 50.degree. C. for about 120 minutes. The dried spheroids so obtained
were sieved and the fraction with diameter greater than 0.71 mm and less
than 1 mm was obtained.
B. In like manner, long acting sustained release spheroids may be prepared
from other dihydropyridine calcium channel blocker including nifedipine,
niludipine, nitrendipine, nisoldipine, nimodipine, and felodipine.
THE INVENTION--EXAMPLE 3
1.8 kg of nicardipine hydrochloride, 0.72 kg of lactose monohydrate, 0.75
kg of microcrystalline cellulose and 0.75 kg of Eudragit L100-55 (brand
copolymer of methacrylic acid and ethylacrylate) were blended together in
a Hobart mixer. A solution of 0.015 kg of sodium hydroxide and 0.015 kg of
polysorbate 20 in water was added to the dry mixture and the wet mass was
further mixed. The wet mass was extruded through a Nica extruder having a
screen size of 0.8 mm and the extrudate was rotated on a Nica spheroniser
at about 400 rpm for about 3 minutes. The spheronized particles were then
dried in an Aeromatic fluid bed drier at 50.degree. C. for about 120
minutes. The dried spheroids so obtained were sieved and the fraction with
diameter greater than 0.71 mm and less than 1.00 mm was obtained.
405 g of the spheroids were fluidized in an aeromatic fluid bed drier at
about 30.degree. C. and a suspension containing 39.06 g of Eudragit L30D
(brand copolymer of methacrylic acid and ethylacrylate), 5.859 g of talc
and 1.172 g of triethylcitrate in 48 g of water was sprayed onto the
spheres. The spheres were then dried at about 50.degree. C. for about 10
minutes and blended with 4.5 g of talc and 0.45 g of colloidal silica.
In a like manner, long acting sustained release spheroids may be prepared
from other dihydropyridine calcium channel blockers including nifedipine,
niludipine, nitrendipine, nisoldipine, nimodipine and felodipine
EXAMPLE 4
This example shows typical dissolution rates in a standard USP paddle test
of a comparison standard release and uncoated long acting nicardipine
compositions prepared as described in Examples 1 and 2 in comparison with
topical dissolution rates of a coated long acting composition according to
this invention prepared as described in Example 3.
The resulting data, set out in Table 1 which follows, whow the necessary
additional protection conferred by the coat by virtue of its ability to
further reduce the dissolution rate of nicardipine formulation under
conditions where the nicardipine shows good solubility. Under these
circumstances and at the given dose the high dissolution rates found with
the uncoated formulation will manifest themselves as unacceptable high
peak plasma levels which are often associated with the onset of unpleasant
side effects. These high plasma levels are shown in Example 5 and
accompanying Tables 2 and 3.
TABLE 1
______________________________________
PERCENT OF NICARDIPINE DISSOLVED
STANDARD UNCOATED COATED
RELEASE LONG-ACTING LONG-ACTING
TIME (20 mg) (120 mg) (120 mg)
(min) (a) (b) (c) (b) (c)
______________________________________
5 56
10 98
20 99
30 99 29 19 3 17
60 100 44 42 5 32
120 63 73 9 54
180 76 85 12 68
240 85 90 16 75
360 95 94 22 85
480 101 97 29 91
720 103 97 39 97
______________________________________
(a) Dissolution medium is pH 4.5 citrate buffer
(b) Dissolution medium is 0.1 M hydrochloric acid
(c) Dissolution medium is pH 7.4 phosphate buffer +2% Polysorbate 20*, th
brand of polyoxyethylene 20 sorbitan monooleate available from Imperial
Chemical Industries. A standard USP paddle dissolution test was run at 50
rpm in 1,000 ml of the specified medium.
*Polysorbate 20 is the brand of polyoxyethylene 20 sorbitan monooleate
supplied by Imperial Chemical Industries.
EXAMPLE 5
In this example the post-administration plasma nicardipine concentrations
given by these formulation are compared. The three formulations are
(A) a capsule containing uncoated marumes of Example 2;
(B) a capsule containing coated marumes of Example 3; and
(C) a capsule containing coated marumes of Example 3 together with standard
fast release powder of Example 1.
Plasma samples were withdrawn at intervals and analysed for nicardipine
concentration by chromatography. The results are tabulated as measured
plasma concentrations and derived pharmacokinetic parameters in Tables 2
and 3 respectively. The results are also shown graphically in FIG. 1 which
depicts measured plasma concentrations versus time profiles for
formulations A, B and C.
The data shown in FIG. 1 and Tables 2 and 3 demonstrate that while all
three formulations are of a sustained release nature, in as much as they
give detectable plasma levels 24 hours after dosing, the formulation
containing the uncoated product only achieves this at the expense of
unacceptably high peak plasma levels e.g., 101.0 ng/ml as compared to 59.2
ng/ml and 60.2 ng/ml for the coated (improved) formulation (Table 2).
Tables 2 and 3 and FIG. 1 also clearly indicate that the presence of a
fast release loading dose (formulation C) is not required with this
improved formulation. Thus only a one component, the coated marumes,
capsule fill is necessary which simplifies both processing and subsequent
quality control of the product. The improved formulation (formulation B)
in addition to having a desirable lower maximum plasma level than the
uncoated product also has an equally desirable 70% higher minimum plasma
concentration than the uncoated product further indicating the superiority
of this improved product for once daily administration.
TABLE 2
______________________________________
NICARDIPINE PLASMA CONCENTRATIONS IN
HUMANS (ng/ml)
FORMULATION C
(COATED
FORMULA- FORMULA- MARUMES
TIME TION A TION B 100 mg +
POST (UNCOATED (COATED standard
ADMIN. MARUMES) MARUMES) powder)
(H:MIN)
(90 mg) (120 mg) (20 mg)
______________________________________
0:00 3.36 3.02 3.54
0:20 3.48 3.17 3.87
0:40 9.02 4.35 41.9
1:00 14.0 5.45 37.9
1:30 11.0 7.02 29.3
2:00 13.8 13.1 26.5
3:00 85.2 37.5 39.9
4:00 101.0 52.8 57.9
6:00 45.0 59.2 60.2
8:00 19.6 31.2 27.6
10:00 10.8 14.5 18.0
12:00 8.08 10.2 11.5
16:00 4.74 6.10 6.94
20:00 3.05 3.27 3.67
24:00 1.75 2.99 2.92
______________________________________
TABLE 3
______________________________________
DERIVED PHARMACOKINETIC DATA
FORMULA- FORMULA- FORMULA-
TION A TION B TION C
______________________________________
C.sub.max (ng/ml)
106 73.8 72.6
C.sub.24 (ng/ml)
1.75 2.99 2.92
T.sub.max (h)
3.83 4.83 5.00
AUC (ng .multidot. h/ml)
472 419 487
______________________________________
*The derived pharmacokinetic parameters were calculated by standard
methods well known to anyone experienced in the art (Pharmacokinetics by
Gibaldi and Perrier, publisher Marcel Dekker 1975).
The uncoated marumes of U.S. Pat. No. 4,940,556 are well suited for
twice-daily administration. However the data here show that administration
of uncoated marumes at an increased dose suitable for once-daily
administration as indicated by measurable plasma levels at 24 hours after
dosing, results in unacceptably high peak plasma levels which range from
43% to 70% higher than the proposed improved formulation. Such higher
plasma levels would be more likely to result in higher incidences of side
effects. The improved formulation according to the present invention gives
a desirable 70% higher plasma level at 24 hours clearly demonstrating its
superior sustained release properties for once daily dosing.
These data illustrate the following advantages over the comparison
compositions:
(a) Uses no solvents
(b) Readily amenable to large scale production
(c) Most importantly does not rely on a coat only to provide sustained
release, i.e., it has a double sustained release action of both coat and
marume with rate controlling binder. This reduces the absolute dependency
of the integrity of the coat in the prevention of dose dumping resulting
in a product which is considerably safer to use.
EXAMPLE 6
In this example the typical daily plasma nicardipine concentrations
following administration of two formulations are compared. The
formulations are two capsules containing 30 mg and 20 mg, respectively, of
standard fast release powder ("pdr") of Example 1 given at 8 hourly
intervals and a capsule containing 120 mg of coated marumes of Example 3
given at 24 hourly intervals. The results are shown graphically in FIG. 2.
These data demonstrate that once daily administration (administration at 0
hours) of the coated marumes gives maximum plasma concentrations
comparable with those given by three daily doses (administered at 0, 8 and
16 hours) of the standard powder, but without the frequent peaks and
thoughs associated with the standard powder.
Top